Clozapine has a unique clinical pharmacology. Yet the usual explanations for its superiority have not stood the test of time.
It is not blockade of serotonin receptors, nor weak blockade of dopamine D2 receptors. Nor is it an action at other dopamine receptors or at noradrenaline receptors.
Clozapine is sticky at muscarinic acetylcholine receptors. Some of its most common side-effects are at muscarinic receptors in the body… and are highly atypical of an antipsychotic drug. For instance, stimulation of saliva resulting in hypersalivation. Or stimulation of the bladder resulting in nocturnal enuresis.
This suggests that clozapine is not simply blocking muscarinic receptors. In some tissues, it actually appears to stimulate them.
How do we test that idea?
Well, the cleanest approach is to express cloned human muscarinic receptors in a cell line and to examine the drug-receptor interaction directly.
In such assays, clozapine does indeed stimulate muscarinic receptors. It behaves as a partial agonist, stickier for the receptor than acetylcholine itself…but weaker once it gets there.
In stark contrast other antipsychotics either block muscarinic receptors or leave them alone. Clozapine is unique in being a partial agonist at muscarinic receptors.
The crucial test of that hypothesis is fairly intuitive. Does a drug which stimulates muscarinic receptors, but which leaves dopamine receptors untouched, have antipsychotic properties?
This is challengining because stimulation of muscarinic receptors in the body produces major autonomic side-effects. Drugs just weren’t available until recently… But three years ago, Cobenfy solved that problem.
Cobenfy is composed of a partial muscarinic agonist called xanomeline alongside a molecule which protects muscarinic receptors in the rest of the body.
And as you might know, it works. And that changed everything. For the first time, we have a muscarinic-based antipsychotic. Or is that true?
Surely Clozapine was the first member of this class all along. Clozapine was the prototype of this new muscarinic class.
The next phase
Going forward, a major question for psychiatry is whether Xanomeline reproduces the full benefits of clozapine…. without the baggage. If it does, that is a major advance.
If it doesn’t, then perhaps the ideal treatment for psychosis is combining what we now know to be two distinct antipsychotic mechanisms.
Fairly easy to test. Say, Xanomeline plus low dose amisulpride (or quetiapine). Put the two together and you may have recreated clozapine. And a safe clozapine at that.
Clozapine has long been the most effective antipsychotic for people whose symptoms do not respond to standard treatments, yet no one has been able to fully explain why. For years, psychiatry has assumed that antipsychotic drugs work mainly by blocking dopamine or serotonin receptors, even though clozapine does not fit comfortably into either explanation. In a recent article, we suggest that the answer may have been hiding in plain sight: clozapine behaves very differently from other antipsychotics in the body’s cholinergic (acetylcholine) system, a difference that turns out to be central rather than incidental (Morrison et al 2025).
This matters because it helps make sense of both clozapine’s unmatched effectiveness and the recent success of a new generation of drugs that do not rely on dopamine blockade. These muscarinic-acting treatments appear to follow the same principle clozapine hinted at decades ago, but with better tolerability. If this approach continues to hold up, it could change how we understand psychosis and mark the beginning of a genuinely new era in antipsychotic treatment (Morrison et al 2025).
Widely regarded as a classic in modern psychiatry, Eric Kandel’s “Biology and the Future of Psychoanalysis” occupies a distinctive place at the intersection of neuroscience and depth psychology. Published in 1999 by a Nobel Prize–winning neuroscientist, in the final years of the “Decade of the Brain,” the paper reflects a moment when advances in brain science were reshaping psychiatry’s intellectual landscape. Rather than casting biology as a reductive alternative to psychoanalysis, Kandel argues that these advances offer the empirical tools psychoanalysis has long lacked, enabling its foundational concepts—such as the unconscious, and early experience—to be examined scientifically.
The paper is especially compelling in its careful use of neuroscientific research, including work on memory and stress-related neurobiology, to demonstrate how psychoanalytic ideas can be mapped onto identifiable neural systems. This integration preserves the explanatory depth of psychoanalysis while situating it within a testable biological framework. In doing so, Kandel offered a forward-looking vision for psychiatry, suggesting that the future intellectual vitality of psychoanalysis depends on its engagement with modern neuroscience rather than its isolation from it.
Many unfortunate individuals suffer year after year of depression. Depressive illness becomes the defining feature of their lives, as one tablet after another fails, and the psychotherapies reveal themselves as blunt instruments. For decades, psychopharmacologists have sought a new class of antidepressant, based on new mechanisms, rather those which target the brainstem-derived neuromodulators, serotonin, noradrenaline and dopamine. Finally, there has been a breakthrough. Ketamine, a molecule familiar to the anaesthetists, has repeatedly showed efficacy against stubborn depression. And recently, the s-enantiomer (esketamine) has been fast-tracked for clinical use in the USA after positive results in phase III trials. Ketamine necessitate intravenous administration, whereas esketamine, an intranasal spray, represents a much more practical option for wider clinical use.
The Neurophysiology: Extended consciousness, brain wiring & the personality
Ketamine blocks a receptor for glutamate, the main fast excitatory neurotransmitter in the cortex, thalamus and limbic system. This is the NMDA receptor channel, which is one of the most celebrated components in modern neuroscience, critical for short and long-term plasticity at glutamate excitatory synapses (Collingridge and Bliss, 1995). Channel opening, and the inward flux of Ca2+, are the prime movers in boosting the strength of individual glutamate synapses, of which there are over 15,000 converging on a single neuron. Over the timeframe of seconds, NMDA receptor activation is essential for supporting conscious mental activity in the vast neural network (Ingram et al., 2018). NMDA receptor activation can also set in train processes which ultimately lead to the long-term structural enhancement of glutamate synapses, the basis for learning and memory. The personality is believed to emerge and develop as the neural network is sculpted and fine-tuned, at the level of individual synapses, by lived experience (Kandel, 1998)(DeFelipe, 2006).
Ketamine impacts upon the neural network, stimulating neurotrophic pathways and enriching neural connectivity, in keeping with the modern idea that depression stems from impoverished connectivity (McEwen et al., 2015).
The NMDA Receptor. Glutamate (GLU) and glycine (GLY) activate the NMDA receptor causing channel opening and influx of Na+ and Ca2+. Calcium is a second messenger which activates various from of plasticity. The NMDA receptor is a crucial starting point for working memory and epsiodic memory in the CNS. Ketamine blocks the pore of the channel, impeding Na+ and Ca2+ influx.
The Psychophysiology: The complete transformation of lived experience & re-birth
Given the physiological importance of glutamate NMDA receptor channels for brain functioning, it is not surprising that ketamine, which blocks the channel pore and impedes the influx of Ca2+, has a profound effect on the psyche. Effects are dose-related. The anaesthetists make use of the fact that ketamine blocks conscious mental content, to the extent that surgical procedures can be carried out in otherwise awake patients, who can support their own respiration. Pain physicians also utilise ketamine, in the knowledge that chronic pain syndromes probably stem from an ingrained plastic adaptation in the cortical areas which support pain perception. For psychiatrists, there is range of ketamine doses which elicit such a complete transformation in lived experience, that some have labelled those experiences as psychotic. In fact, those experiences go much further the usual connotations of psychosis as hallucinations and delusions. Descriptions include, the cessation of time, the dissolution of the ego, near-death experiences and spiritual experiences, perhaps best demonstrated by the use of a plant-derived NMDA receptor channel blocker (ibogaine) as ceremonial entheogen in West Africa.
(There was hope and considerable investment in the idea that a new class of antipsychotic treatments, based on glutamate, could be developed, but this drug-discovery effort failed to materialise in end-stage trials. For depression however, the story has been much more encouraging, and the next phase is now unfolding.)
In West Africa, there is use of a plant-derived NMDA channel blocker called ibogaine. Ibogaine is in the same pharmacological class as ketamine. Ibogaine is used in tribal ceremony to transform conscious experience.
The Upside of NMDA channel blockers in depression
A number of clinical properties of NMDA channel blockers are highly favourable, in comparison to the older antidepressants. Above all, the NMDA channel blockers have a very rapid impact upon depression, within hours, compared to several weeks for the older drugs. The NMDA channel blockers can also impact upon the most stubborn depressions, in which the older drugs, psychotherapy and even ECT proved ineffective and frustrating. Finally, the NMDA channel blockers have a rapid anti-suicidal effect, which as experience accrues, may come to represent a specific indication in acute settings.
The downsides: NMDA channel blockers in depression: Real, potential & hyped
All effective treatments carry a downside in terms of side effects, but in comparison to much older psychiatric therapies such as clozapine, lithium and benzodiazepenes, ketamine/esketamine are remarkably safe. Of course, many patients will be put off by the idea of having psychedelic experiences and there is also a worry over possible diversion, given that ketamine is used as a club drug by people actually seeking those very same psychedelic experiences. Compared to other drugs of abuse however, ketamine addiction is a rare phenomenon, and withdrawal reactions are not recognised. Heavy, unrestrained use of ketamine is known to cause bladder dysfunction, but this appears to be a feature of recreational misuse rather than in the clinic, where bladder function can easily be monitored.
It has been suggested that ketamine works in the same way as an opiate. Naturally this has led to scare stories, given the recent experience of opiate prescribing in the USA. However, the psychopharmacology of ketamine and opiates are quite different at the behavioural and molecular level. The most serious adverse effect of opiates is respiratory depression and death, because of overstimulation of mu receptors. Ketamine, an NMDA receptor channel blocker, does not cause respiratory depression, and the analgesic effects of ketamine in the CNS do not appear to be mediated via mu opiate receptors.
Perhaps the major downside of NMDA channel blockers is that the antidepressant effects typically diminish after about one week. With repeated sessions, this can be extended to about three-four weeks. A major challenge for psychopharmacologists is how to extend the duration of the antidepressant effect. In the UK, ketamine treatment for depression has been available at the NHS Warneford hospital in Oxford for about a decade. Many patients who benefitted from an initial course of intravenous ketamine return for maintenance sessions, in which the gap between sessions is individually tailored. These are patients whose lives were hitherto dominated by depression, and who found no relief from standard approaches. With maintenance treatment, they can enjoy depression free lives. Hopefully, the time-limited nature of the antidepressant effect will eventually be understood and solutions developed.
Esketamine, as an intranasal spray, now offers the possibility of more widespread and perhaps even routine clinical use for many others disabled by clinical depression. Although there are concerns, it should be realised that the prescribing of NMDA channel blockers will take place within a therapeutic relationship in which close attention is paid to how an individual patient responds, the swift recognition of any adverse effects and provision of supportive psychotherapy (and perhaps in time, even a specialised adjuvant psychotherapy). Measures to prevent diversion can be put be put in place.
History Repeats: A new Golden Age of Psychopharmacology
The old tricyclic antidepressants translated into the clinic within three years of the first positive findings in 1957, in what has been termed the Golden age of Psychopharmacology. Aside from the benefits to thousands of individual patients, a new era of neuroscience was initiated, which revealed much of the physiology of serotonin and noradrenaline (Leiberman,, 2015). Over the ensuing decades, the basic science of brainstem derived neuromodulators and monoamine-based therapeutics developed in tandem, leading to the development of safer alternatives, (the SSRIs in 1971). The positive findings with ketamine and esketamine in depression are ushering in a similar scenario. This time of course, the tools of molecular neuroscience are available, so that the pace of discovery should be quicker, and at a much more fundamental level. Already the therapeutic benefits of NMDA channel blockers are being made available for patients whose lives have been dominated by depression. Just as happened for the older antidepressants, refinements will be made over the coming years with the joint efforts of laboratory based pharmacologists and psychiatrists who treat depressed patients. Novel administration regimes, adjuvant psychotherapies, and new candidate molecules targeting other components of glutamate neurotransmission are likely to appear.
Collingridge GL and Bliss TVP (1995) Memories of NMDA receptors and LTP. Trends in Neurosciences18(2): 54–56. DOI: 10.1016/0166-2236(95)80016-U.
Ingram R, Kang H, Lightman S, et al. (2018) Some distorted thoughts about ketamine as a psychedelic and a novel hypothesis based on NMDA receptor-mediated synaptic plasticity. Neuropharmacology142: 30–40. DOI: 10.1016/j.neuropharm.2018.06.008.
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McEwen BS, Bowles NP, Gray JD, et al. (2015) Mechanisms of stress in the brain. Nature Neuroscience18(10): 1353–1363. DOI: 10.1038/nn.4086.
The previous post in this series described the symptoms of schizophrenia. Here we turn to the causes of schizophrenia. There has been major progress in this area over the last twenty years. A number of factors have been identified which carry a risk for schizophrenia. Some of these factors are genetic, others impact during the course of life.
Usually schizophrenia emerges in late adolescence or early adulthood, as the intellect, personality and neural networks are being sculpted. The population risk is slightly less than 1%, with a slight excess of male sufferers (1.4:1). Males also tend to show a more severe pattern of illness, with more impoverishment of the personality and psychological decline.
Risk Factor Categories
The risk factors for schizophrenia can be grouped into several categories (Figure 1). The perinatal category includes hypoxic and nutritional insults to the developing brain in-utero. The second category includes being brought up in city environment, particularly for immigrants. The third category includes drugs of abuse, specifically strong cannabinoid CB1 receptor agonists. Finally, there is the genetic category, which can be subdivided into single nucleotide polymorphisms (SNPs) and copy number variants (CNVs).
Figure 1. Risk factors for schizophrenia.
Genetic risk factors
It has long been recognized that schizophrenia runs in families (Figure 2), but until the last decade attempts to identify specific genes floundered. Technological advances have revolutionized the field. It is now feasible to screen an individual’s DNA at every base pair (A, T, C, G) in every chromosome. Variants (say the substitution of an A for a T) are called single nucleotide polymorphisms (SNPs) when they occur in at least 5% of the overall population.
In the technique known as GWAS (genome wide association study) tens of thousands of patients are compared against tens of thousands of controls. So far, 145 SNPs have been shown to confer risk for schizophrenia (Figure 3). Each SNP on its own carries a very small risk, but they are common in the population, and their effects are additive. Two SNPs of considerable interest are the gene for a calcium channel (CaV1.2) and the gene for a protein called complement C4a.
Figure 3. Single nucleotide polymorphisms which confer a risk for schizophrenia.
The second major breakthrough in schizophrenia genetics are copy number variants (CNVs). Copy number variants are deletions or duplications of a long stretch of DNA, typically incorporating half a dozen genes or so. So far eight CNVs which confer a risk for schizophrenia have been identified. Each of these CNVs carry a very high risk. A CNV of considerable interest is NRXN1 (Figure 4).The NRXN1 protein forms a physical bridge which stabilses synaptic connections in the brain. The NRXN1 story provides strong evidence for a long-held theory that the pathology of schizophrenia stems from abnormal connectivity within neural networks.
Figure 4. Copy number variants which carry a risk for schizophrenia.
We can recap. A number of factors confer risk for the development of schizophrenia. These can be categorized into several categories – perinatal, environmental, cannabinoid CB1 drugs, and genes. The gene category includes SNPs (such as, complement C4a, the calcium channel CaV1.2) and CNVs (such as NRXN1). In the next post in this series we will look at the neurobiology of these components and cannabinoid CB1 drugs.
The 
